Proteasome inhibitors and uses thereof

A compound of Formula (I): [structure] wherein R is H or C 1-6 alkyl; R 1 is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, aryl, heteroaryl, non-aromatic heterocycle, and non-aromatic heterocycle substituted with ═O; R 2 is independently selected at each occurrence thereof from the group consisting of H, C 1-2 alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and —(CH 2 ) m C(O)NHR 4 , wherein alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl; R 3 is selected from the group consisting of H, —SO p R 5 , —C(O)(CH 2 ) k Ar, —SO 2 Ar, —SO 2 C 3-8 cycloalkyl, —C(O)(CH 2 ) k Het, and —C(O)C 1-6 alkyl, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen or C 1-6 alkyl; R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 3-8 cycloalkyl, wherein C 3-8 cycloalkyl can be optionally substituted with —CF 3 ; R 5 is selected from the group consisting of alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl, wherein alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl; k is 0 or 2; m is 1 or 2; n is 1, 2, or 3; and p is 1 or 2; or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

A method of treating cancer, autoimmune disorders, or inflammatory disorders in a subject or for providing immunosuppression, said method comprising: administering to the subject in need thereof a compound of the Formula (I): [structure] wherein R is H or C 1-6 alkyl; R 1 is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, aryl, heteroaryl, non-aromatic heterocycle, and non-aromatic heterocycle substituted with ═O; R 2 is independently selected at each occurrence thereof from the group consisting of H, C 1-2 alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and —(CH 2 ) m C(O)NHR 4 , wherein alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl; R 3 is selected from the group consisting of H, —SO p R 5 , —C(O)(CH 2 ) k Ar, —SO 2 Ar, —SO 2 C 3-8 cycloalkyl, —C(O)(CH 2 ) k Het, —C(O)C 1-6 alkyl, and —C(O)OC 1-6 alkyl, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen or C 1-6 alkyl; R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 3-8 cycloalkyl, wherein C 3-8 cycloalkyl can be optionally substituted with —CF 3 ; R 5 is selected from the group consisting of alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl, wherein alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl; k is 0 or 2; m is 1 or 2; n is 1, 2, or 3; and p is 1 or 2; or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, wherein the autoimmune disorder is selected from the group consisting of arthritis, colitis, multiple sclerosis, lupus, systemic sclerosis, and sjögren syndrome; the cancer is selected from the group consisting of multiple myeloma, lymphoma, and other hematological cancers; the inflammatory disorder is Crohn's disease or ulcerative colitis; and the immunosuppression is provided for transplanted organs or tissues or is used to prevent transplant rejection and graft-verse-host disease.

A method of inhibiting chymotryptic β5i in a cell or a tissue, said method comprising: providing a compound of Formula (I): [structure] wherein R is H or C 1-6 alkyl; R 1 is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, aryl, heteroaryl, non-aromatic heterocycle, and non-aromatic heterocycle substituted with ═O; R 2 is independently selected at each occurrence thereof from the group consisting of H, C 1-2 alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and —(CH 2 ) m C(O)NHR 4 , wherein alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl; R 3 is selected from the group consisting of H, —SO p R 5 , —C(O)(CH 2 ) k Ar, —SO 2 Ar, —SO 2 C 3-8 cycloalkyl, —C(O)(CH 2 ) k Het, —C(O)C 1-6 alkyl, and —C(O)OC 1-6 alkyl, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen or C 1-6 alkyl; R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 3-8 cycloalkyl, wherein C 3-8 cycloalkyl can be optionally substituted with —CF 3 ; R 5 is selected from the group consisting of alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl, wherein alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl; k is 0 or 2; m is 1 or 2; n is 1, 2, or 3; p is 1 or 2; and contacting a cell or tissue with the compound under conditions effective to inhibit chymotryptic β5i.

A method of treating infectious disease in a subject, said method comprising: administering to the subject in need thereof a compound of the Formula (I): [structure] wherein R is H or C 1-6 alkyl; R 1 is selected from the group consisting of monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl, wherein monocyclic and bicyclic aryl, biphenyl, monocyclic and bicyclic heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, aryl, heteroaryl, non-aromatic heterocycle, and non-aromatic heterocycle substituted with ═O; R 2 is independently selected at each occurrence thereof from the group consisting of H, C 1-2 alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and —(CH 2 ) m C(O)NHR 4 , wherein alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl; R 3 is selected from the group consisting of H, —SO p R 5 , —C(O)(CH 2 ) k Ar, —SO 2 Ar, SO 2 C 3-8 cycloalkyl, —C(O)(CH 2 ) k Het, —C(O)C 1-6 alkyl, and —C(O)OC 1-6 alkyl, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from halogen or C 1-6 alkyl; R 4 is selected from the group consisting of H, C 1-6 alkyl, and C 3-8 cycloalkyl, wherein C 3-8 cycloalkyl can be optionally substituted with —CF 3 ; R 5 is selected from the group consisting of alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl, wherein alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, —OH, —NO 2 , —CF 3 , —OC 1-6 alkyl, alkyl, alkenyl, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic heterocyclyl; k is 0 or 2; m is 1 or 2; n is 1, 2, or 3; and p is 1 or 2; or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.